Download Twisting arms to angiotensin receptor blockers/antagonists: the turn

CURRENT OPINION
European Heart Journal (2011) 32, 19–22
doi:10.1093/eurheartj/ehq382
Twisting arms to angiotensin receptor
blockers/antagonists: the turn of cancer
Massimo Volpe 1,2*, Michel Azizi 3,4,5, A.H. Jan Danser 6, Genevieve Nguyen 7,
and Luis M. Ruilope 8
1
Received 21 July 2010; revised 24 August 2010; accepted 7 September 2010; online publish-ahead-of-print 21 October 2010
Introduction
Treatment of cardiovascular disease has achieved spectacular
targets in the last 30 years, significantly contributing to the dramatic increases in life expectancy. In contrast, in the recent
years, very few pharmacological innovations have been proposed, most likely because of the escalating costs of drug clinical
development and by the reduced needs of innovation in this
field.
Angiotensin receptor blockers/antagonists (ARBs) have represented one of the major novel class of drugs reaching the therapeutic use for cardiovascular disease indication. Given the
extremely high prevalence of hypertension, the leading indication
for ARBs, prescription of this class of drugs has increased to
very high levels. It is calculated that about 200 million individuals
are treated with ARBs on our planet and that this class covers
25% prescription of antihypertensive agents. Even though this
may be due to intensive marketing activity, it is also related to
their ‘friendly’ use recognized by both doctors and patients,
being the best tolerated class among cardiovascular drugs,1,2 and
to rigorous and impressive clinical development. In fact, beyond
the 15-year clinical experience by physicians and the consequent
long-term drug surveillance by the authorities of healthcare
systems worldwide, until today more than 300 000 patients have
been strictly monitored for periods averaging from 3 to 5 years
in clinical trials performed in numerous different clinical settings
[including hypertension, high cardiovascular risk, diabetes, heart
failure, myocardial infarction (MI), renal failure, stroke, and atherosclerosis].3,4 In all these studies, adverse reactions ascribed to
ARBs have generally been less than any comparator, and similar
to placebo. Besides the setting of clinical trials, these drugs have
been extensively investigated as indicated by more than 12 100
scientific publications on PubMed at the date of 3 July 2010,
using only the keywords Angiotensin Receptor Antagonists and
Angiotensin Receptor blockers.
Angiotensin receptor blockers/
antagonists clinical development: a
long and winding road
During their clinical development and progressive application in
therapy, several questions have been raised about the efficacy
and safety of ARBs. An initial doubt, which has been only partially
answered, relates to their equivalence/superiority to angiotensinconverting enzyme-inhibitor (ACE-I) in the treatment of congestive heart failure (CHF) and post-MI; the results of the ELITE I5
and II studies6 that compared a low-dose ARB (losartan 50 mg
o.d.) with a very high dose of the ACE-I captopril (50 mg t.i.d.),
showed no difference in efficacy but less side effects with the
ARB in CHF. Similar results were obtained in post-MI in the OPTIMAAL7 and VALIANT8 studies, in which relatively low dosages of
ARBs (losartan 12.5 –50 mg and valsartan 20–160 mg daily,
respectively) were used as compared with the dosages of captopril
(50 –150 mg daily). Finally, in Val-Heft9 and CHARM,10 some
specific benefits of ARBs were described. These observations
were not considered convincing enough to replace ACE-I, as the
‘gold standard’ therapy for these conditions, especially in view of
the long-term and vast experience with ACE-I and their lower
cost, as well as because, for ethical reasons, no direct comparisons
between ARBs and ACE-I were performed.
The turn of myocardial infarction
A second, much more serious, hurdle for ARBs and especially for
their safe use in clinical therapy was raised with regard to a
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
* Corresponding author. Tel: +39 06 3377 5654, Fax: +39 06 3377 5061, Email: [email protected]
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2010. For permissions please email: [email protected].
Downloaded from eurheartj.oxfordjournals.org at Hospital Central Cruz Roja on January 5, 2011
Division of Cardiology, Department of Clinical and Molecular Medicine, 2nd Faculty of Medicine, University of Rome ‘La Sapienza’, Sant’Andrea Hospital, Via di Grottarossa,
1035-39, 00189 Rome, Italy; 2IRCCS Neuromed, Pozzilli, Italy; 3Université Paris Descartes, Faculté de Médecine, Paris F-75006, France; 4Assistance Publique des Hôpitaux de Paris,
Hôpital Européen Georges Pompidou, Paris F-75015, France; 5INSERM, CIC 9201, Paris F-75015, France; 6Division of Vascular Medicine and Pharmacology, Department of Internal
Medicine, Erasmus MC, Rotterdam, The Netherlands; 7Institut National de la Santé et de la Recherche Médicale (INSERM, Unit 833 and Collège de France, Experimental Medicine
Unit, 11 place Marcelin Berthelot, 75005 Paris, France; and 8Hypertension Unit, Hospital 12 de Octubre, Madrid, Spain
20
The turn of cancer
In spite of these difficulties as well as of a series of mega trials with
ARBs that generated substantially neutral results, especially in highrisk patients,14,16 ARBs are prescribed worldwide for a number of
indications beside hypertension with no major safety concerns,
apart from being contraindicated in pregnancy, renovascular hypertension, and very severe chronic kidney disease. However, on the
basis of some isolated experimental reports, suggesting a role of
AT1 receptors and AT2 receptors in processes involved in carcinogenesis (cellular proliferation, angiogenesis, and tumour progression) and the unexpected findings of significantly higher
death rate by cancers in the candesartan arm of the CHARM programme,10 Sipahi et al.17 undertook and published a meta-analysis
based on the evaluation only of studies with ARB reporting cancer
data, to gain insights on their effect on the development of solid
cancers and cancer death. The conclusion of this study, published
a few weeks ago in Lancet Oncology,17 suggested that ARBs are
associated with a ‘modest increase’ (1– 2% absolute risk) of new
cancers as compared with the control group (7.2 vs. 6.0%, RR
1.08, CI 1.01–1.15, P ¼ 0.016).
Given the high emotional impact that this initial and preliminary
report on such a sensitive endpoint may have on physicians currently prescribing ARBs, we felt that it is important to critically
discuss some aspects of this report and, most of all, examine the
biological data that support the assertion that ARBs may increase
cancer risk.
With all due respect to a ‘stand-alone’ report, based on a limited
meta-analytical approach, we cannot refrain from making a few
general comments before discussing biological validity: (i) studies
with a follow-up of 1 year and arbitrarily including at least 100
patients were considered. The longest follow-up was 5 years.
Now, if one considers the time-course of cancer onset in response
to well-known carcinogenic agents, this appears as a major conceptual limitation for a reasonable interpretation of a relatively shortterm treatment with ARBs. There is little, if any, biological plausibility that a drug exposure of a few years only would increase the
risk of new cancer diagnosis. Cigarette smoking, which is one of
the most powerful risk factors for lung cancer, will require 10
years or longer exposure to significantly increase the risk of lung
cancer. Thus, it is very unlikely that the short-term drug exposure
over the course of a clinical trial ARBs would have a clinically
meaningful effect; (ii) the lack of information on individual patient
data from any of the trials considered and on the timing of
cancer, as acknowledged by the authors, is a major drawback of
the analysis. This limitation is aggravated by the consequent lack
of information on sex, age, smoking, and previous neoplastic
history; (iii) in the studies used for the analysis, adjudication of
cancer diagnosis was not uniform; (iv) the increased risk of
cancer found by Sipahi in their meta-analysis is completely driven
by ONTARGET, and within this study, only by the telmisartan/
ramipril combination vs. ramipril.14 In contrast, telmisartan did
not increase cancers as compared with ramipril. In the studies
comparing telmisartan with placebo (TRANSCEND and the
PROFESS), cancer rates were equivalent. These observations
raise reasonable doubts in the interpretation, also in view of the
fact that the rates of new cancers in these studies were quite consistent with that of the general population; and (v) in none of the
studies considered, there was a higher risk of cancer death in the
ARBs groups compared with the control groups with the exception of a borderline significance in CHARM-overall.10
As mentioned before, the authors recognize most of these
limitations of their study, and other important methodological
aspects would deserve to be discussed thoroughly. One important
flaw of this meta-analysis is that the majority of large international
trials involving ARBs (at least 16)4 have not been considered.
These data which represent thousands of patients treated with
ARBs should now be made available to perform a state-of-the-art
meta-analysis. The simple addition of VALUE data, for instance,
eliminates the reported difference in cancer incidence between
ARBs and controls (http://www.theheart.org/article/1091359.
do#bib_3). Nonetheless, the authors suggest that their findings
should prompt a prospective ‘ad-hoc’ study. Even more, the
accompanying editorial18 states that ‘in the interim we should
use great caution in the use of ARB’ which are ‘overprescribed
as a result of aggressive marketing’. This kind of conclusions and
statements may obviously generate anxiety, if not panic, among
millions of patients regularly taking ARBs as well as among
doctors.
This type of alarming situation is not new in the history of antihypertensive drugs, ever since the use of reserpine was associated
with an increased risk of breast cancer more than 30 years ago, the
question of antihypertensive drugs and cancer has not come to
rest. Indeed, the cancer –hypertension connection has been discussed for a long time. Cancer is frequently occurring in the
aging population in which hypertension is also more frequently
present. In addition, hypertension has been associated with an
excess rate of cancer mortality related to all types of tumours
[adjusted pooled OR (95% CI): 1.23 (1.10–1.36)].19 Over the
past decades, antihypertensive drugs have been often associated
with cancer.20 Beta-blockers have been associated with lung
cancer, calcium-channel blockers with cancer in general, and thiazide diuretics with renal cell carcinoma and colon cancer. The use
of antihypertensive drugs was even reported to be associated with
an increased risk of glioma. In most instances, the excess risk is
small, does not persist after adjustment on confounding factors,
and is not supported by biochemical experimental or epidemiological data.
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presumed increased risk of MI due to their use. This alarm
appeared in the British Medical Journal with a subtitle ‘these drugs
may increase myocardial infarction and patients may need to be
told,’ which generated significant concern and disappointment in
both physicians and patients, and received significant diffusion in
the media.11 Unsurprisingly, this was amplified by healthcare authorities in some countries, probably with the good intention to ‘jeopardize’ an expensive drug class and indirectly support other less
expensive antihypertensive drugs. This alarm, based on an incomplete meta-analysis,11 has been diminished by thorough metaanalyses,12,13 as well as by direct comparisons with ACE-I,14 and
even, by the same author, by a vast analysis of a database.15 Also
the claim of clinical incompatibility of ARBs with beta-blockers in
heart failure, based on a relatively small subgroup in Val-Heft,9
was denied by the much larger experience of CHARM.10
M. Volpe et al.
ARBs and risk of cancer
Since a retrospective study21 showed that the use of
ACE-inhibitors potentially protects against cancer, albeit controversial,22 blockers of the renin-angiotensin system have experienced a remarkably favourable record in this regard. In most
studies and meta-analyses, the risk of cancer with renin-angiotensin
system (RAS) blockers was either equal or lower than with their
comparators including placebo.22 Thus, the report by Sipahi
et al.17 showing a modestly increased risk of new cancer diagnosis
with ARBs, is unexpected and certainly warrants scrutiny and
further investigation.
An important aspect to discuss, therefore, is whether there is sufficient biological plausibility to support the hypothesis that ARBs
favour cancer development, and whether the postulated mechanism advocated by Sipahi et al. 17 in their discussion has any solid
basis. This mechanism proposes that the rise in angiotensin
(Ang) II during ARB treatment will activate the non-blocked AT2
receptors, thereby inducing tumour angiogenesis.
Indeed, several tumoural cell types have been reported to
express Ang II receptors.23 These include melanoma, brain, lung,
pancreatic, renal, breast, ovarian, bladder, and prostate cancer.
Moreover, in high-grade astrocytomas, tumour Ang II receptor
expression was associated with a high grade of malignancy,
increased cellular proliferation, and angiogenesis, and thus predicted poor prognosis.24
As demonstrated in the Matrigel model in mice, Ang II induces
angiogenesis via activation of the vascular endothelial growth
factor (VEGF)/endothelial NO synthase (eNOS) pathway.25 This
involves AT1 rather than AT2 receptors, since only ARBs
blocked this process.25 In line with this observation, ACE-I,26
ARBs,27 and a recombinant antibody (R6313/G2) against the AT1
receptor28 displayed antineoplastic activity and inhibited angiogenesis in various tumoural experimental models.
With regard to the potential significance of the stimulation of
unopposed AT2 receptors in patients treated with ARBs, the
role of the AT2 receptor in cancer is controversial. This may
depend on the experimental model and the cancer type. In the
model of subcutaneously transplanted syngeneic xenografts pancreatic ductal carcinoma cells, tumour growth was more rapid
and the tumour vasculature was significantly enhanced in AT2
receptor knock-out mice than in wild-type animals.29 In addition,
the growth of pancreatic ductal carcinoma cells in vitro was
decreased when cultured with AT2 receptor gene transfected
fibroblasts.29 Furthermore, overexpression of AT2 receptor
induced cell death in lung adenocarcinoma cells via activation of
apoptosis.30 Taken together, these data suggest that AT2 receptors
stimulation results in an antitumour effect. This may be due to the
fact that AT2 receptors exert anti-angiogenic effects by interfering
with VEGF/eNOS-mediated endothelial cell migration and tube
formation.31 Yet, AT2 receptor gene deficiency attenuated susceptibility to tobacco-specific nitrosamine-induced lung tumourigenesis by down-regulating the level of transforming growth factor
b,32 thus supporting a pro-tumour effect of AT2 receptors. A possible explanation for these contradicting observations is that AT2
receptors may achieve an AT1 receptor-like phenotype under
pathological conditions, e.g. inducing vasoconstriction/angiogenesis
rather than vasodilation/anti-angiogenesis.33 Finally, studies with
the AT2 receptor agonist compound C21 so far have not produced
any alert for cancer, although it should be acknowledged that this
has been generally involved in short-term studies only.
Angiotensin receptor blockers/antagonists as well as ACE-I
increase plasma and tissue concentrations of Ang (1– 7). In a
human lung tumour xenograft model, athymic mice with
tumours treated with Ang-(1–7) by osmotic mini pumps for 28
days had a 30% reduction in tumour volume associated with
reduced tumoural cyclooxygenase-2 expression and a decreased
vessel density.34 Angiotensin (1–7) has anti-angiogenic effects in
the chick chorioallantoic membrane model and reduces VEGF-A
expression in tumours.35 In vitro, Ang-(1 –7) inhibits lung cancer
cell growth through the activation of the MAS receptor and this
effect cannot be prevented by either AT1 nor AT2 receptor
antagonists.36
Angiotensin receptor blockers/antagonists and ACE-I differently
affect the level of N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP),
induced in plasma and tissues. N-acetyl-seryl-aspartyl-lysyl-proline
is a natural inhibitor of pluripotent haematopoietic stem cell proliferation,37 is formed in vivo by enzymatic cleavage of the
N-terminus of thymosin beta4 by prolyl oligopeptidase (POP),
and is physiologically degraded by the N-terminal domain of
ACE.37,38 Its accumulation during ACE inhibition may partially
mediate the cardioprotective effect of ACE-inhibitors. However,
Ac-SDKP has also been suggested to be pro-angiogenic:
Ac-SDKP stimulates endothelial cell proliferation, migration, and
tube formation in a dose-dependent manner and increases myocardial capillary density in rat hearts with MI.39 It also stimulates
an angiogenic response in the chicken embryo chorioallantoic
membrane,40 in the abdominal muscle of the rat, and in a model
of surgically induced hind-limb ischaemia.41 N-acetyl-serylaspartyl-lysyl-proline levels are increased in haematologic and
solid malignancies (breast, colon, head and neck, kidney, lung,
skin, ovary, and prostate) and enhanced activity of POP is also
detected in cancer tissues.42 Thus, in theory at least, ARBs
(which do not alter Ac-SDKP concentrations) should not stimulate
angiogenesis via this pathway, whereas ACE-I could.
Finally, the rise in renin per se, as occurring during any type of
RAS blockade, may have detrimental consequences. Indeed, renin
as well as its precursor prorenin bind to the (pro)renin receptor
[(P)RR] and trigger intracellular signalling in an Ang II-independent
manner. Interestingly, the (P)RR has recently been shown to be a
component of the Wnt receptor complex and to be essential for
the signalling of the canonic Wnt-b-catenin pathway although not
necessarily in a (P)RR-dependent manner.43 Since the Wnt-bcatenin pathway is essential in embryonic and adult stem cell
biology and therefore in cancer, one could imagine that the
increased levels of renin and prorenin, as occurring during ARB
therapy (as well as during any other type of RAS blockade!), are
responsible for augmented Wnt-b-catenin signalling and cancer.
However, up to now, the role of the (P)RR in the Wnt-b-catenin
signalling has only been demonstrated in Xenopus 43 and clearly,
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Angiotensin receptor blockers/
antagonists and cancer: a closer
look at potential mechanisms
21
22
more work is needed to substantiate these findings in higher
mammals.
Conclusions and perspectives
Disclosures
The authors wish to clearly state that this article was projected and
written independently of any kind of support or influence from any
other parties, including pharmaceutical industries. Furthermore,
they have no active financial conflict of interest that may have
affected the content of the article.
Acknowledgements
The authors wish to thank Francesca Palano, MD, for the precious
help in preparing the manuscript.
Conflict of interest: M.V.: active research grant from Novartis;
participation to international advisory boards of Bayer Schering
Pharma and Daichii-Sankyo; honoraria lectures in symposia by
Daichii-Sankyo and sanofi-aventis. M.A. has consulted for and has
received research funding and honoraria from Novartis,
sanofi-aventis, and Actelion within the past 2 years. A.H.J.D. has
received lecture fees and research grants from Novartis and
Vitae Pharmaceuticals. G. N. has received lecture fees and research
grants from Novartis and Institut de Recherche Servier. L.M.R. is
advisor/speaker for Astra-Zeneca, Bristol Myers Squibb, Bayer,
Novartis, Menarini, Recordati, Takeda, Daiichi-Sankyo, Otsuka.
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Unfortunately, blood pressure still remains uncontrolled in many
patients and exposes them to the risk of having a heart attack or
stroke. To get blood pressure under control, we need to extensively use for long term all available antihypertensive drug
classes, particularly those better tolerated by patients. The news
that some of these antihypertensives potentially could cause
cancer is alarming for patients who are on these drugs and could
motivate them to abruptly discontinue treatment.
In any event, although we cannot avoid nor want to avoid this
information being shared with our patients, it should be done prudently and with sufficient balance by responsible news media. A
similar emphasis is often not given to the beneficial effects of
these drugs. Thus, drawing the line between the benefits and the
risks at the individual patient level may leave the prescribing physician and the patient in total perplexity!
The alarming conclusions of the paper by Sipahi et al. 17 and of
the related commentary18 do not seem appropriate, especially in
consideration of the fact that the meta-analysis was neither
thorough nor based on a systematic selection of the cancer endpoint in the included studies. At this time, we do not think that
the data of the analysis of Sipahi et al. 17 are sufficient to undertake
a prospective study exploring a causal link between ARBs (or a
specific ARB) and cancer, especially in consideration of the lack
of consistent biological mechanisms and the predicted duration
of the study. At the same time, we believe a detailed scrutiny of
all available databases by health authorities and scientific groups
should be encouraged.
In this regard, very recently, the Food and Drug Administration
(FDA) in US drug safety communication on ongoing safety review
of the ARBs and cancer (online available on http://www.fda.gov/
Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsand
Providers/ucm218845.htm), has not concluded that ARBs increase
the risk of cancer. At this time, FDA believes that the benefits of
these medicines continue to outweigh the potential risks. Food
and Drug Administration recommends that these drugs continue
to be used as indicated in their approved labels and that the patients
should not stop their use unless told by physicians.
M. Volpe et al.
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